Bromoergolines and process for preparing the same

ABSTRACT

wherein R4 is aryl, substituted aryl, heterocycl, or substituted heterocycl; or   wherein R5 is R3 is hydrogen or methyl. Novel bromoergoline derivatives having high adrenolytic activity, and a method for their preparation. These ergoline derivatives are of the following structural formula:   WHEREIN R1 is hydrogen or methoxy; R2 is -CONH2; -CH2X wherein X is -NH2, -OH, or

United States Patent [1 1 Arcari et a1.

[4 1 Sept. 9, 1975 1 BROMOERGOLINES AND PROCESS FOR PREPARING THE SAME [75] Inventors: Giuliana Arcari; Luigi Bernardi;

Alfredo Glasser; Bianca Patelli, all of Milan, Italy [73] Assignee: Farmitalia Societa Farmaceutici Italia, Milan, Italy [22] Filed: June 21, 1973 [21] Appl. No.: 372,320

Primary Examiner-G. Thomas Todd Attorney, Agent, or Firm-Hubbe1l, Cohen & Stiefel [5 7] ABSTRACT Novel bromoergoline derivatives having high adrenolytic activity, and a method for their preparation. These ergoline derivatives are of the following structural formula:

wherein R is hydrogen or methoxy;

R is CONH CH X wherein X is NH -OH, or

wherein R is aryl, substituted aryl, heterocycl, or substituted heterocycl; or

wherein R is R is hydrogen or methyl.

15 Claims, N0 Drawings BROMOERGOLINES AND PROCESS FOR gen or methyl;

PREPARING THE SAME and further is directed to a method of preparing the foregoing compounds.

The compounds of the present invention exhibit a BACKGROUND OF THE INVENTION 5 high fldrenolytic activity DESCRIPTION OF THE PREFERRED The present invention is directed to a new class of EMBODIMENTS bromoergolinc derivatives which are useful in therapy,

and to a process for their preparation The compounds of the present invention are prepared according to the following reaction scheme:

R .R 3 a. bromlne reduction 1 V (hydrobromic acid) 4 l A Bl-T Br R l (1;) (III) (I) SUMMARY OF THE INVENTION wherein R R and R are as defined above. The present invention is directed to new compounds More particularly, a derivative of formula II is bromihaving the following structural formula: nated, optionally in the presence of hydrobromic acid,

to give a 2,l3-dibromoderivative of formula III. By reaction with sodiumborohydride, in the presence of a cobaltous salt, such as, for example, cobaltous chloride (CoCl at a temperature between about 30 and +30C, there occurs selective removal of the bromine atom from the 2-position to thereby transform the product into the corresponding l3-bromoderivative of formula I.

The selectivity and the linearity of the reaction are believed to be unique.

The foregoing ergoline derivatives, substituted in the 13-position by a bromine atom, show a markedly higher adrenolytic activity and a much lower toxicity than the nonsubstituted compounds. By contrast, bromine substitution in the 2-position, or dibromine substitution in the 2- and l3-positions, results in a reduction of the adrenolytic and antienteraminic activity.

The adrenolytic activity of the compounds of the present invention was studied in vitro and in vivo and was compared with that for the corresponding wherein R is hydrogen or methoxy;

2 is 2; 2 wherein X is 2. other derivatives referred to above.

01' Thus, the activity of 1,6-dimethyl-8 B( 5 bromonicotinoyloxy-methyl)-l 3bromo-10oz- O methoxyergoline (A), was compared with that of the ll R non-brominated derivative (B), arbltrarily indicated as having an activity equal to 100, wlth that of the 2- wherein R, is aryl, substituted aryl, heterocycyl, bmmodefivfltive and With that Of the or substituted heterocycyl; or dibfomodefiviltivc The results, reported in the table below, show the marked increase in adrenolytic activity for the compound monosubstituted in the l3-position.

In the in vitro" studies, it has been shown that the wherein R is hydrogen or lower alkyl; and R is hydroadrenolytic effect of derivative (A) is markedly superior to that of derivative (B). Thus, the seminal small bladder tissue to which derivative (B) was added requires only two washings with physiological solution to completely remove the adrenolytic effect of derivative (B) from said tissue. On the other hand, the same tissue having derivative (A) added thereto requires ten washings with physiological solution to completely remove the adrenolytic effect of derivative (A).

l g of l-methyll ()a-methoxy-Ll 3- dibromodihydrolysergol was dissolved in 60 ml of methanol, to which were added, at 20C, 2.5 g of cobaltous chloride and thereafter 2 g of sodium borohydride.

After 30 minutes at 2oc, the whole was diluted in water and extracted with ethyl acetate. The solvent was evaporated off under vacuum and the residue was crys- TAB LE Adrenolytic activity Adrenolytic activity in vitro (seminal "in vivo" small bladder in (protection from Compound Ref. m.p. guinea-pig) death by adrenaline) l,6-dimethyl-8-B-(5 bromonicotinoyloxymethyD-lO-a-methoxy- 1 ergoline B 138-139 lOO I 1 ,6-dimethyl-2-bromo-8-[3- ('-bromonicotin0yloxymethyl)-l0-amethoxyergoline C 143-145 35 1,6-dimethyl-2,l 3-dibromo-8-B-(5-bromo nicotinoyl0xymethyl)- l0-a-methoxyergoline D 188- 1 90 5 7O l,6-dimethyl-8-, 3-(5'- bromonicotinoyloxymeth yl)- l 3-bromol O-amethoxyergoline A 178-] 80 120 200 The following examples will further illustrate the invention. Unless otherwise indicated, all parts given are by weight.

EXAMPLE I To 3 g of methyl l0 a-methyoxydihydrolysergate (formula 11; R CH O-; R COOCH R H) dissolved in 60 ml of acetic acid there was added, with shaking, 1 gram mole of bromine. After 10 minutes, 1 ml of pyridine was added and the whole was concentrated under vacuum. The solvent was evaporated off and the residue was crystallized, first from benzene and subsequently from methanol. 2.9 g of methyl 2-bromolOa-methoxydihydrolysergate, m.p. 2102l2C, were obtained, which were dissolved in 50 ml of acetic acid, and 1 mole of bromine was added thereto. After 10 minutes, I ml of pyridine was added and the whole was evaporated under vacuum. The residue was made alkaline by the addition of aqueous ammonia and extracted with chloroform. The chloroform was removed under vacuum and the residue was chromatographed on silica gel. By eluting the silica gel with chloroform, 3.9 g of methyl 2,13-dibromo-l0 a-methoxydihydrolysergate, m.p. 230232C, were obtained.

1.5 g of this compound were dissolved in 90 ml of methanol and there were added at C, 3.7 g of cobaltous chloride and then 3 g of sodium borohydride. After minutes at -20C, the product was diluted with water and extracted with ethyl acetate. The solvent was evaporated under vacuum and the residue was crystallized from acetone. Methyl l3-bromo-l0amethoxydihydrolysergate was obtained, m.p. 163- 165C. Yield (Y)=75%.

EXAMPLE 2 Operating as described in Example 1, however starting with l-methyl lOct-methoxydihydrolysergol (formula II; R =CH O; R CH OH; R CH,,) there was obtained l-methyl-2, l 3-dibromo- I004- methoxydihydrolysergol, m.p. 203205C (Y 70%).

tallized from acetone. 0.6 g of l-methyl-lOa-rnethoxyl 3-bromodihydrolysergol was obtained, m.p. 196l 98C.

EXAMPLE 3 Operating as in Examplel, however using as the starting compound dihydrolysergol (formula II; R =H; R CH OH; R,,=H), there was obtained 13- bromodihydrolysergol, m.p. 248250C (Y 80%).

EXAMPLE 4 Operating as in Example I, however starting with lmethyldihydrolysergol (formula II; R,=H; R CH- OH; R CH there was obtained 1-methyl-l3- bromodihydrolysergol, m.p. 203205C.

EXAMPLE 5 Operating as in Example l, however starting with dihydrolysergamide (formula II; R =H; R -CONH R =H there was obtained 1 3- bromodihydrolysergamide, m.p. 2082l0C (Y= EXAMPLE6 Operating as in Example 1, however starting with 1-methyldihydrolysergamine (formula ll; R,=H; R CH NH R -CH there was obtained l-methyll3-bromodihydrolysergamine, m.p. 7880C (Y 60%).

EXAMPLE 7 After 30"minutcs at C. the whole was diluted with water and taken up with ethyl acetate. The ethyl acetate extract was washed with water and then evaporated under vacuum. The residue was crystallized from acetone/petroleum ether and 0.95 g of methyl 1 3-bromodihydrolysergate was obtained. m.p. 190l 92C.

EXAMPLE8 Operating as in Example 1. however starting with dihydrolysergie acid (formula II; R,=H; R COOH-, R -=H), there was obtained 2,13-dibromodihydrolysergic ,acid, m.p. 300C (Y 72% By reaction of this compound with sodium borohydride and cobaltous chloride, 13-bromodihydrolysergic acid was obtained.

EXAMPLE 9 0.5 g of l-methyll 0a-methoxy-l 3- bromodihydrolysergol (formula I; R ==CH;,O; R

EXAMPLE 1O Operating as in Example 9, however employing 5- bromonicotinoyl chloride rather than pyrrol-2- carboxylic acid chloride, there was obtained l-methyl- IOa-methoxyl 3-bromodihydrolysergol 5-bromonicotinate- [.i.e., l,6-dimethyl-8a(5- bromonicotinoyloxymethyl l 3-bromolOa methoxyergol inel, m.p. l78l80 C (Y 90%).

EXAMPLE 1 1 Operating as in Example 10, using l?methyl-l3- bromodihydrolysergol (formula I R =H; R CH- OH; R CH;,), there was obtained l-methyll3- bromodihydrolysergol 5-bromon icotinate, m.p. l75177C (Y 86%).

EXAMPLE 12 To 0.6 g of l-methyl-13-bromodihydrolysergamine (formula I; R =H; R CH NH R CH;,) dis solved in 5 ml of pyridine was added 0.4 g of benzoyloxycarbonylchloride at 0C. After one night at room temperature, the product was evaporated under vacuum, taken up with water, made alkaline with aqueous ammonia, and extracted with ethyl acetate.

The solvent was evaporated off and the residue was chromatographed on silica gel. 0.4 g of l-methyl-13- bromocarbobenzoxydihydrolysergamine (amorphous) was obtained, which. upon treatment with maleic acid quaternized the o-nitrogen atom yielding a crystal-line acid maleate salt melting at 98-l00C.

Variations can, of course, be made without departing from the spirit and scope of the invention.

Having thus described our invention, what is desired to be secured by Letters Patent and hereby claimed is:

l. A method of making a compound of the following structural formula:

wherein R is hydrogen or methoxy;

where R; is phenyl, pyrrolyl or S-bromopyridyl; or

wherein R is hydrogen or lower alkyl; and

R is hydrogen or methyl;

this method comprising brominating a compound of the formula:

wherein R R and R are as defined above, to yield a compound of formula (III) wherein R R and R are as defined above, and reacting said compound ("1) with sodiumborohydride, in

the presence of a cobaltous salt, at a temperature between about 3()C and +C, to thereby selectively remove a bromine atom from the 2-position and thereby yield a l3-bromo derivative of formula (I).

2. The method of claim 1 wherein said bromination of the compound of formula (ll) is carried out in the presence of hydrobromic acid.

3. A compound of the formula:

wherein R is hydrogen or mcthoxy;

R is -CONH CH X wherein X is NH OH,

wherein R is phenyl, pyrrolyl or S-bromopyridyl; or

wherein R is hydrogen or lower alkyl; and

R is hydrogen or methyl.

4. A compound as defined in claim 3 which is methyl 1 3bromodihydrolysergate.

5. A compound as defined in claim 3 which is 1- methyl- 1 Oa-methoxyl 3-bromo-dihydrolysergol.

6. A compound as defined in,claim 3 which is 13- bromodihydrolysergamide.

7. A compound as defined in claim 3 which is 13- bromodihydrolysergol.

8. A compound as defined in claim 3 which is 1- methyl- 1 3-bromo-dihydrolysergol.

9. A compound as defined in claim 3 which is 1- methyl- 1 3-bromol ()a-methoxy-dihydrolysergate.

10. A compound as defined in claim 3 which is lmethyll 3-bromo-dihydrolysergamine.

11. A compound as defined in claim 3 which is l3-bromodihydrolysergic acid.

12. A compound as defined in claim 3 which is 1- methyl- 1 ()a-methoxyl 3-bromo-dihydrolysergol 2-pyrrolcarboxylate.

13. A compound as defined in claim 3 which is 1,6- dimethyl-8,8-( 5-bromonicotinoyl-oxymethy] )-1 3- bromol Oa-methoxy-ergoline 14. A compound as defined in claim 3 which is 1- methyl- 1 3-bromo-dihydrolysergol 5bromonicotinate.

15. A compound as defined in claim 3 which is lmethyl-13-bromo-carbobenzoxydihydrolysergamine.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,90 4 Dated September 9, 1975 It is certified that error 'appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Title Page Tight side, lines 6-7 after the formula: "heterocycl" should read heterocycyl (both occurrences); right side,

last line "R is R should read R is hydrogen or lower alkyl; and R is Column 3, line 34: "dmethyoxydihydrolysergate" should a read d-methoxydihydrolysergate Column 5, line 14: "(Y 7270)" should read (Y 70% line 38: "l,6-dimethyl-8d(5"'" should read l,6-dimethyl-8B(5'- line 61: "crystal-line" should read crystalline CERTIFICATE OF CORRECTION Patent No. 3,904,634 Dated September 1-975 In entor-(s) et a]. Page 2 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

I' I O I Column 6, line 35: "where" should read wherein Signed and Scaled this thirteenth a 0 [SEAL] D y f January 1976 Attest:

RUTH. C. MA'SON C. MARSHALL DANN Anestmg Offlce' Commissioner oflarents and Trademarks -g UNITED STATES PATENT OFFICE I Notice of Adverse Decision in Interference In Interference No. 99,385, involving Patent No. 8,904,634, G. Arcari, L. Bernardi, A. Glasser and B. Patelli, BROMOERGOLIN ES AND PROC- ESS FOR PREPARING THE SAME, final judgment adverse to the patentees was rendered June 14, 197 7 as to claims 3, 4L and 11.

[Ofioz'al Gazette September 20, 1977.] 

1. A method of making a compound of the following structural formula:
 2. The method of claim 1 wherein said bromination of the compound of formula (II) is carried out in the presence of hydrobromic acid.
 3. A COMPOUND OF THE FORMULA:
 4. A compound as defined in claim 3 which is methyl 13-bromodihydrolysergate.
 5. A compound as defined in claim 3 which is 1-methyl-10 Alpha -methoxy-13-bromo-dihydrolysergol.
 6. A compound as defined in claim 3 which is 13-bromodihydrolysergamide.
 7. A compound as defined in claim 3 which is 13-bromodihydrolysergol.
 8. A compound as defined in claim 3 which is 1-methyl-13-bromo-dihydrolysergol.
 9. A compound as defined in claim 3 which is 1-methyl-13-bromo-10 Alpha -methoxy-dihydrolysergate.
 10. A compound as defined in claim 3 which is 1-methyl-13-bromo-dihydrolysergamine.
 11. A compound as defined in claim 3 which is 13-bromodihydrolysergic acid.
 12. A compound aS defined in claim 3 which is 1-methyl-10 Alpha -methoxy-13-bromo-dihydrolysergol 2-pyrrolcarboxylate.
 13. A compound as defined in claim 3 which is 1,6-dimethyl-8 Beta -(5''-bromonicotinoyl-oxymethyl)-13-bromo-10 Alpha -methoxy-ergoline.
 14. A compound as defined in claim 3 which is 1-methyl-13-bromo-dihydrolysergol 5-bromonicotinate.
 15. A compound as defined in claim 3 which is 1-methyl-13-bromo-carbobenzoxydihydrolysergamine. 